Mosaic monosomy 7 in a male infant with ambiguous genitalia and multiple congenital anomalies DM LaGrave1, CW Booth2, DA Rita2, ME Aston1, KB Geiersbach1,4, S. Shetty1,4, LR Rowe5, ST South1,3,4 1Cytogenetics and Molecular Cytogenetics, ARUP

1
Mosaic monosomy 7 in a male infant with ambiguous
genitalia and multiple congenital anomaliesDM
LaGrave1, CW Booth2, DA Rita2, ME Aston1, KB
Geiersbach1,4, S. Shetty1,4, LR Rowe5, ST
South1,3,4 1Cytogenetics and Molecular
Cytogenetics, ARUP Laboratories, Salt Lake City,
UT 2Lutheran General Hospital, Park Ridge, Ill,
3Department of Pediatrics, University of Utah,
Salt Lake City, UT, 4Dept of Pathology,
University of Utah, Salt Lake City, UT, 5ARUP
Institute for Clinical and Experimental
Pathology, Salt Lake City, UT

Differential Diagnosis
Case Report

• Constitutional mosaic monosomy 7
• Congenital anomalies suggest a constitutional
  anomaly
• Deletion of the long arm of ch7 is associated
  with hypospadias, microphallus, and small scrotum
• Explains all clinical findings
• Pre-neoplastic change restricted to the bone
  marrow
• Chronic, unexplained anemia, lymphopenia and
  thrombocytopenia
• Monosomy 7 is the most common finding childhood
  MPS/MDS
• Monosomy 7 syndrome?
• Requires separate explanation for congenital
  anomalies

• Male Hispanic infant delivered at 27w4d by
  emergency c-section due to IUGR, decreased fetal
  movement and bradycardia.
• Clinical findings
• Ambiguous genitalia
• Perineoscrotal hypospadias with bifid scrotum
• Bilateral clubfoot
• Hyperpigmentation
• Small, echogenic kidneys with pyelectasis
• PDA
• Brain MRI Normal for age
• Small thymus
• Slow growth
• Repeated episodes of sepsis, apnea and
  bradycardia
• Low cortisol
• Persistent absolute lymphopenia and
  thrombocytopenia
• Chronic anemia of unknown etiology
• At 5 months of age (2 months - corrected age) he
  developed hypernatremia and became unresponsive.
  The parents elected to discontinue extraordinary
  measures, and the infant died.

Fig 2 FISH (CEP7) demonstrating a single signal
for chromosome 7 in one interphase cell and 2
signals in both an interphase cell and a
metaphase cell

• Monosomy 7 Syndrome 1, 2, 3
• Monosomy 7 syndrome (Mo7s) has been described as
  a well-defined myeloproliferative disorder with
  prominent bone marrow dysplasia and
  hepatosplenomeagly existing primarily in young
  children
• There is a significant disparity in the male to
  female ratio, with 70 of affected children being
  male
• There are many clinical and epidemiologic
  similarities between Mo7s and juvenile chronic
  myelogenous leukemia. Monosomy7 is associated
  with genetic disorders of myelopoiesis that carry
  a high risk of myeloid leukemia (Fanconi anemia,
  severe congenital neutropenia, Shwachman-Diamond
  syndrome) as well as with constitutional
  conditions (neurofibromatosis, type 1 Down
  syndrome - possibly)
• Familial bone marrow monosomy 7 has been observed
  in some families as a unique finding as well as
  being associated with cerebellar ataxia in others
• Loss of chromosome 7, alone, is not sufficient
  for transformation to full leukemia

Fig 3 Banded chromosomes demonstrating 2 copies
of chromosome 7
Discussion
Do the findings in this child represent a
constitutional mosaic monosomy 7 or a
pre-neoplastic change in the bone marrow only
with concurrent, unrelated congenital anomalies?
If the mosaicism is constitutional, then there
are two possible etiologies 1) monosomy rescue
and 2) post-zygotic loss. Monosomy rescue was
ruled out by STR analysis (Fig 4), leaving the
possibility that a constitutional monosomic cell
line began at some point during embryogenesis.
If the monosomic cell line is restricted to the
bone marrow, that would indicate that the
congenital anomalies seen in the infant were
coincidental and unrelated to the aCGH
findings. Is this a possible new syndrome? We
propose that the constellation of findings in
this child represent a new genetic syndrome of
development requiring a cell-line during
embryogenesis that becomes monosomic for
chromosome 7. The monosomic cell line could
theoretically be due to monosomy rescue or
post-zygotic loss, and its presence would be
predicted to cause congenital anomalies of
varying severity depending on the timing of
rescue/loss and the level of mosaicism in
different tissues at critical points in
development. As the bone marrow is one tissue
that can support a monosomy 7 cell line with
little effect on fetal development, hyperplasia
of the bone marrow leading to thrombocytopenia,
anemia and/or lymphopenia would be expected to be
a key finding in this syndrome. Genetic males
with this syndrome would be expected to have some
level of feminization of their external genitalia
- possibly secondary to adrenal insufficiency.
But the degree of feminization, if present, would
depend on the variations in timing and tissues
affected by the chromosome loss. Genetic females
would be predicted to have normal genitalia but
might demonstrate decreased cortisol levels in
infancy.

• Conclusions
• Male, Hispanic infant with mosaic monosomy 7,
  possibly limited to the bone marrow, and
  ambiguous genitalia
• One other case , with very similar findings,
  described in the literature
• A second case in the literature describing a girl
  with gonadal dysgenesis and monosomy 7 (45,XY,-7
  in bone marrow analysis only) possibly
  representing a milder form of this proposed
  syndrome?
• We propose that the rare association of ambiguous
  genitalia with monosomy 7 syndrome may be due to
  the prenatal loss of one chromosome 7 in affected
  children and would therefore represent a new
  genetic syndrome of development
• Key features of the syndrome would be 1) monosomy
  7 syndrome with hyperplasia of the bone marrow 2)
  genetic males with some degree of feminization of
  the external genitalia 3) /- dysmorphic features
  4) /- adrenal hypoplasia
• The key finding of ambiguous genitalia in males
  with mosaic monosomy 7 is similar to males with
  partial deletions of 7q suggesting that the
  mosaic monosomy 7 seen in the bone marrow was
  originally due to loss of chromosome 7 in an
  embryonic cell line